Open Access
Molecules, volume 26, issue 7, pages 2026
Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling
Krivitskaya Alexandra V
1
,
Khrenova Maria G.
1, 2
Publication type: Journal Article
Publication date: 2021-04-02
PubMed ID:
33918209
Organic Chemistry
Drug Discovery
Physical and Theoretical Chemistry
Pharmaceutical Science
Molecular Medicine
Analytical Chemistry
Chemistry (miscellaneous)
Abstract
Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.
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Citations by publishers
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Multidisciplinary Digital Publishing Institute (MDPI)
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5 publications, 45.45%
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1 publication, 9.09%
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Frontiers Media S.A.
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1 publication, 9.09%
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- We do not take into account publications that without a DOI.
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Krivitskaya A. V., Khrenova M. G. Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling // Molecules. 2021. Vol. 26. No. 7. p. 2026.
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Krivitskaya A. V., Khrenova M. G. Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling // Molecules. 2021. Vol. 26. No. 7. p. 2026.
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TY - JOUR
DO - 10.3390/molecules26072026
UR - https://doi.org/10.3390%2Fmolecules26072026
TI - Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling
T2 - Molecules
AU - Krivitskaya, Alexandra V
AU - Khrenova, Maria G.
PY - 2021
DA - 2021/04/02 00:00:00
PB - Multidisciplinary Digital Publishing Institute (MDPI)
SP - 2026
IS - 7
VL - 26
PMID - 33918209
SN - 1420-3049
ER -
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@article{2021_Krivitskaya,
author = {Alexandra V Krivitskaya and Maria G. Khrenova},
title = {Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling},
journal = {Molecules},
year = {2021},
volume = {26},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
month = {apr},
url = {https://doi.org/10.3390%2Fmolecules26072026},
number = {7},
pages = {2026},
doi = {10.3390/molecules26072026}
}
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Krivitskaya, Alexandra V., et al. “Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling.” Molecules, vol. 26, no. 7, Apr. 2021, p. 2026. https://doi.org/10.3390%2Fmolecules26072026.
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